Over the course of aging, the functioning of the central nervous system of dogs, like other mammals, shows a general deterioration. Behaviorally, this deterioration is manifested in a variety of ways, which include decreased exploratory behavior, disturbances in sleep, deficits in housetraining, general restlessness, difficulties in attention, and an overall decrease in motivation. In severe cases, these deficits constitute a canine form of dementia. Behavioral problems in elderly dogs impair the quality of life of the dog, and also decrease the enjoyment of the dog by its master.
The presence of these problems has resulted in the recognition and diagnosis of age-dependent behavioral problems in dogs. The potential importance in sensencent dogs was indicated in a survey by conditions (Chapman, et al., 1990) of 26 aged dogs, greater or equal to 10 years of age. The most common complaints from pet owners were destructive behavior in the house, inappropriate urination or defecation and excessive vocalization. In some cases, pet owners noticed an increase in separation anxiety. In each instance, these dogs were normal when younger. Moreover, these behavioral problems could not be linked to any other medical condition. In fact, one sign of canine senility frequently used by veterinarians is the existence of urinary incontinence, which typically results in the pet owner's decision to euthanize their pet (Mosier, et al., 1988).
These age-dependent behavioral problems also have problematic effects on service dogs. These are highly skilled dogs that are specially trained to carry out a uniquely important function. They include: seeing eye dogs which are trained to help the blind; hearing dogs, which help physically disabled individual who seek increased mobility and independence; special skilled dogs, who are trained on an individual basis based on the person's special needs; and military working dogs, which are trained for a variety of special military functions. The value of these dogs stems in part from the cost of their training. For example, the Lyons foundation in Oakville, Ontario, Canada estimates that the cost to train a single dog is about $20,000. These dogs are typically retired between 7-8 years of age because they become less attentive and slow down.
Age-dependent behavioral problems can be evaluated objectively by neuropsychological tests. The inventors have conducted several studies that were aimed at analyzing learning and memory processes of aged canines. They initially reported that aged dogs performed more poorly than young dogs on a variety of visual base neuropsychological tests (Milgram et al., 1995) and on a spatial memory test (Head et al., 1995). The inventors have subsequently found that aged dogs do particularly poorly on size discrimination learning and reversal task (Head et al., 1998).
More recently, the inventors reported on the basis of an extensive analysis of 54 dogs that level of behavioral functioning of aged dogs could be further broken down into subsets of successful agers, animals with mild impairment, and animals showing severe impairment (Adams et al., 1999). The inventors are able to distinguish two different subcategories of behavioral impairments learning impairment, which is manifested by difficulty in acquiring neuropsychological tasks, and memory impairment, which is manifested by difficulty in performance of tasks that include a delay interval, in which animals must retain a particular set of information. Animals showing severe impairment show both learning deficits and difficulty in retaining information for interval, longer than about 30 seconds.
These changes in behavior and cognition reflect corresponding age-related changes in the central nervous system (CNS). At a molar level, aged dogs show cortical atrophy (Su et al., 1998), and a corresponding increase in the size of the lateral ventricle. Other degenerative changes also occur in the canine brain over the course of aging. At a more molecular level, age dependent changes include distorted soma, loss of dendritic spines, shrinkage of dendritic branches and tortuous apical dendrites (Mervis et a., 1978). DNA damage is another potential indicator of neuronal dysfunction (this is often precursor to apopototic cell death) (Anderson et al., 1997).
Additionally, the aged canine brain develops pathological deposits of beta amyloid protein, which is similar to that seen in the aged humans. The morphology of A.beta. deposits in aged dog brain is that of a diffuse subtype. These plaques are thioflavin S negative and therefore probably lack .beta.-pleated sheet formation (Cummings, et al., 1993). These diffuse deposits appear to contain intact neurons These observations have been made in a variety of breeds (Wegiel, et al., 1996, Yoshino, et al., 1996), although breeds probably differ in their rate and age of onset of A.beta. deposition (Bobik, et al., 1994).
The inventors have further shown a direct link between these age-related pathologies and dysfunction in learning and memory. One study of the relationship between cognition and neuropathology examined the extent of A.beta. deposition in a group of behaviorally characterized dogs (Cummings et al., 1996). A group of 29 dogs ranging in age from 1.6 to 12-3 years had been tested for reward and object approach learning, visual discrimination and reversal, spatial and object recognition memory. The prefrontal cortex, hippocampus and entorhinal cortex was examined for the extent of A.beta. deposition using image analysis techniques. A discriminant analysis of the test scores indicated that two major clusters were present in the behavioral data, one that was termed procedural-type tasks (reward and object approach learning) and the second termed declarative-type tasks (visual discrimination, reversal and memory tasks). The declarative-type tasks, but not the procedural-type tasks were strongly correlated with A.beta. deposition in both the prefrontal and entorhinal cortices. In fact, up to 68.97% of the variability in test scores could be accounted for by the amount of A.beta. deposition.
In a second study (Head et al., 1998), a more detailed examination was made of 20 beagle dogs ranging in age from 4.5 to 15.3 years of age. These dogs were tested for object and reward approach learning (which the inventors previously established to be independent of A.beta. deposition), object discrimination learning using either a preferred or nonpreferred object and size discrimination learning along with long term retention. Based on the nonhuman primate literature, the inventors predicted that some tasks would be sensitive to frontal lobe pathology (reversal learning, object discrimination learning with a nonpreferred object) and that others would be sensitive to temporal lobe function (size discrimination task). Dogs were first classified as being impaired or unimpaired based upon individual error scores obtained from the learning and memory tasks listed previously. An impaired dog was defined as an animal that obtained an error score falling outside the range of error scores obtained by the young dogs. If dogs were separated on this basis then those old dogs that were impaired had significantly higher amounts of A.beta. deposition. In addition, dogs with impairments in reversal learning and in object discrimination learning with a nonpreferred object accumulated significantly more A.beta. in the prefrontal cortex than unimpaired dogs. This was also true for size discrimination and reward approach learning; impaired dogs had higher amounts of A.beta. in the entorhinal cortex (Head, et al., 1998).
In view of the foregoing, there is a need in the art for a treatment for age-related behavioral problems in dogs.